Hypertension is a major cardiovascular disease risk factor and leading cause of human cardiovascular mortality. Recent molecular genetic studies have revealed a linkage between genes of the renin-angiotensin system (RAS), a major regulator of blood pressure and electrolyte balance in mammals, and hypertension in families. The relative contribution of endocrine and intrinsic tissue RASs to blood pressure regulation are unclear since the individual effects of these different RASs have been difficult to dissect out experimentally. Recent studies demonstrated that knocking out the genes encoding angiotensinogen, the substrate for the RAS enzymatic reaction, regulated in a very high incidence of post-natal mortality, and in occasional survivors, abnormal kidney morphology in mice. These findings suggest that the RAS may also be important in growth and development of the kidney. The aims of this proposal are to utilize novel molecular tools and mouse models to examine the relative contribution of the renal and systemic RASs in the regulation of blood pressure and in the development and function of the kidney. Utilizing available progenitors of transgenic and gene-targeted knock-out models, novel double transgenic mice containing a functional human RAS that is expressed kidney-specifically will be generated. Following molecular and biochemical characterization of this model, blood pressure and renal function will be examined and compared to mice that express the human RAS genes ubiquitously. In separate experiments, these double transgenic models will be bred onto a genetic background in which the angiotensinogen gene has been knocked out in an attempt to complement the lethal defect exhibits by these animals. Frequency of the various genotypes, renal morphology, and renal function will be examined in these mice. Development of these models will provide us a unique opportunity to examine the importance of the intra-renal RAS in the pathogenesis of hypertension and in the development and function of the kidney.